Prevention. European Stroke Initiative.

To determine whether the addition of carotid endarterectomy to aggressive medical management can reduce the incidence of cerebral infarction in patients with asymptomatic carotid artery stenosis. Prospective, randomized, multicenter trial. Thirty-nine clinical sites across the United States and Canada. Between December 1987 and December 1993, a total of 1662 patients with asymptomatic carotid artery stenosis of 60% or greater reduction in diameter were randomized; follow-up data are available on 1659. At baseline, recognized risk factors for stroke were similar between the two treatment groups. Daily aspirin administration and medical risk factor management for all patients; carotid endarterectomy for patients randomized to receive surgery. Initially, transient ischemic attack or cerebral infarction occurring in the distribution of the study artery and any transient ischemic attack, stroke, or death occurring in the perioperative period. In March 1993, the primary outcome measures were changed to cerebral infarction occurring in the distribution of the study artery or any stroke or death occurring in the perioperative period. After a median follow-up of 2.7 years, with 4657 patient-years of observation, the aggregate risk over 5 years for ipsilateral stroke and any perioperative stroke or death was estimated to be 5.1% for surgical patients and 11.0% for patients treated medically (aggregate risk reduction of 53% [95% confidence interval, 22% to 72%]). Patients with asymptomatic carotid artery stenosis of 60% or greater reduction in diameter and whose general health makes them good candidates for elective surgery will have a reduced 5-year risk of ipsilateral stroke if carotid endarterectomy performed with less than 3% perioperative morbidity and mortality is added to aggressive management of modifiable risk factors.

In 1988, we undertook a randomized, placebo-controlled, double-blind trial to investigate the safety and efficacy of low-dose acetylsalicylic acid (ASA), modified-release dipyridamole, and the two agents in combination for secondary prevention of ischemic stroke. Patients with prior stroke or transient ischemic attack (TIA) were randomized to treatment with ASA alone (50 mg daily), modified-release dipyridamole alone (400 mg daily), the two agents in a combined formulation, or placebo. Primary endpoints were stroke, death, and stroke or death together. TIA and other vascular events were secondary endpoints. Patients were followed on treatment for two years. Data from 6,602 patients were analysed. Factorial analysis demonstrated a highly significant effect for ASA and for dipyridamole in reducing the risk of stroke (p < or = 0.001) and stroke or death combined (p < 0.01). In pairwise comparisons, stroke risk in comparison to placebo was reduced by 18% with ASA alone (p = 0.013); 16% with dipyridamole alone (p = 0.039); and 37% with combination therapy (p < 0.001). Risk of stroke or death was reduced by 13% with ASA alone (p = 0.016); 15% with dipyridamole alone (p = 0.015); and 24% with the combination (p < 0.001). The treatment had no statistically significant effect on the death rate alone. Factorial analysis also demonstrated a highly significant effect of ASA (p < 0.001) and dipyridamole (p < 0.01) for preventing TIA. The risk reduction for the combination was 36% (p < 0.001) in comparison with placebo. Headache was the most common adverse event, occurring more frequently in dipyridamole-treated patients. All-site bleeding and gastrointestinal bleeding were significantly more common in patients who received ASA in comparison to placebo or dipyridamole. We conclude that (1) ASA 25 mg twice daily and dipyridamole, in a modified-release form, at a dose of 200 mg twice daily have each been shown to be equally effective for the secondary prevention of ischemic stroke and TIA; (2) when co-prescribed the protective effects are additive, the combination being significantly more effective than either agent prescribed singly; (3) low-dose ASA does not eliminate the propensity for induced bleeding.